Drug addiction is a widespread and severe neuropsychiatric disorder and a major public health concern. It is characterized by loss of behavioral control as the neurobiological processes of learning and memory of information that motivates actions to acquire rewards are overwhelmed by the pharmacological effects of the drug. Combined with other environmental and emotional factors, motivated drug taking leads to compulsive craving, seeking, and taking that define addiction. Reward and addiction learning are mediated by molecular mechanisms of synaptic remodeling at dopaminergic and glutamatergic synapses. Identifying and validating these mechanisms is key to understanding addiction and developing effective strategies to treat it. We have discovered a new mechanism that mediates cognition through the regulation of NMDA receptors (NMDARs). This mechanism involves the modulation of the phosphorylation state of Ser1116 of the NR2B subunit of these receptors. This site is phosphorylated by the neuronal protein kinase, Cdk5. Cdk5 knockout (KO) or inhibition reduces phospho-Ser1116 NR2B, increases cell surface levels of the receptor, increases NMDAR-mediated current, and enhances cognition. Interestingly acute cocaine exposure, causes dephosphorylation of this site, likely facilitating reward learning. In contrast, chronic cocaine exposure potentiates this site, possibly attenuating further learning, thereby contributing to the perpetuation of the addicted state. We believe this mechanism provides a new avenue to understanding the molecular basis of addiction. We propose to study the regulation of this mechanism by cocaine and dopamine signal transduction. We will characterize its modulation during acquisition of self-administration (SA), chronic SA, and extinction after withdrawal from sucrose and cocaine SA in mice. We will define the effects of loss of Cdk5 and reduced phospho-Ser1116 NR2B on sucrose and cocaine SA by temporally and spatially controlled Cdk5 KO. Finally, we will specifically target and validate the role of this mechanism in acquisition, extinction, and reinstatement of sucrose and cocaine SA by viral gene delivery of novel drug-like small interfering peptides that disrupt NR2B-Cdk5 interactions. This translational research will significantly advance our understanding of the mechanisms of addiction and may contribute to the development of treatments to help addicted individuals recover. PUBLIC HEALTH RELEVANCE: Drug addiction is a major neuropsychiatric disorder caused by overstimulation of the brain's natural reward learning pathways, which mediate motivated behaviors. We have discovered a new and important molecular mechanism of synaptic remodeling that involves regulation of the NR2B subunit of NMDA receptors in the brain's reward circuitry that is targeted by cocaine. The goal of this project is to characterize the regulation of this reward learning mechanism, define its contribution to cocaine self-administration, and validate it as a potential target to enhance extinction of drug seeking and taking behavior, so that new treatments for addiction may be developed.